ClinVar Miner

Submissions for variant NM_001184.4(ATR):c.3424A>G (p.Ser1142Gly) (rs149008479)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145303 SCV000192380 uncertain significance Seckel syndrome 1 2013-10-04 criteria provided, single submitter clinical testing
GeneDx RCV000431332 SCV000512213 uncertain significance not specified 2015-08-20 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the ATR gene. The S1142G variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The S1142G variant was not observed with any significant frequency in the 1000 Genomes Project and in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The S1142G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however Glycine has been seen at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000145303 SCV001307573 uncertain significance Seckel syndrome 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001244890 SCV001418141 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 1142 of the ATR protein (p.Ser1142Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs149008479, ExAC 0.08%). This variant has been observed in individuals affected with breast cancer (PMID: 15987455). ClinVar contains an entry for this variant (Variation ID: 157977). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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